Reproductive and Fertility Assessment of Triethylene Glycol Dimethyl Ether in CD-1 Mice when Administered in Drinking Water

Abstract

The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings were not evaluated in accordance with the levels of evidence for reproductive or developmental criteria established by NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of NTP or the U.S. Government.

Triethylene glycol dimethyl ether (TGDME) was tested in the Reproductive Assessment by Continuous Breeding (RACB) protocol as part of a larger effort to evaluate a series of glycol ethers and their structural congeners and metabolites. Previous studies indicated significant prenatal toxicity for TGDME, but reproductive toxicity had not previously been evaluated. Data on body weights, food and water consumption, and clinical signs from the Task 1 dose-range finding study were used to set doses for the continuous cohabitation phase, Task 2, at 0, 0.25, 0.5, and 1.0% EGDME in the drinking water. In combination with a 30-60% consumption increase at the highest concentration, these concentrations produced calculated consumption estimates of nearly equal to 43.8, 87.5, and 175.0 mg/kg/day.

Adult body weights were not changed during Task 2, but at the highest concentration, the number of litters/pair and the number of live pups/litter were reduced by 12% and 50%, respectively. Pup weight adjusted for litter size was reduced at the middle and highest concentrations by 4% and 8%, respectively.

Task 2 was followed by Task 3, a crossover mating to determine the affected sex. This Task re-paired the control and high concentration groups for a week-long mating trial. While all groups showed equal evidence of mating, the group pairing treated females with control males had a 58% reduction in the proportion of females delivering live young. There was an increase in the proportion of dead pups delivered to treated females, and the adjusted pup weight was 6% less than controls.

After these pups were delivered and evaluated, the F0 mice from the control and 1% TGDME groups were killed and necropsied. There was no treatment-related effect on body weights, but body-weight-adjusted liver weight was increased by 17-21% in both sexes. The only other effect noted was a 12.5% decrease in female pituitary weight. Epididymal sperm concentration, motility, and abnormal forms were unchanged.

The effects of TGDME on reproduction in a second generation were not evaluated in this study.

In summary, this study found that triethylene glycol dimethyl ether produced developmental toxicity, as indicated by the reduced pup weights, and female reproductive toxicity, manifested by fewer litters in the high dose group in Tasks 2 and 3.